Hemophilia A is an inherited bleeding disorder caused by mutations in the coagulation factor VIII (FVIII) gene. Treatment involves repeated i.v. infusions of FVIII concentrates throughout the life of the patient, which creates tremendous discomfort and morbidity, requires sustained compliance, and is extremely expensive. In response to these limitations, we seek to develop a novel technology that uses patients' endothelial colony-forming cells (ECFCs) and mesenchymal progenitor cells (MPCs) to bioengineer a vascular network that is capable of sustained FVIII delivery into the bloodstream. Previously, we demonstrated the feasibility of this approach in a murine proof-of-concept study wherein vascular networks that were genetically engineered to express erythropoietin (EPO) corrected anemia in mice (Lin et al., Blood 2011). Based on this foundational work, we propose a technology whereby ECFCs from hemophiliacs are genetically engineered to serve as autonomous drug delivery vehicles in vivo. The envisioned clinical implementation of our approach would involve: 1) isolating ECFCs and MPCs from patients' peripheral blood; 2) inserting a gene encoding for FVIII into ECFCs; and 3) combining both cell types in a suitable hydrogel and injecting the mixture subcutaneously into the patient. Following implantation, cells will self-assemble into a vascular network. This network will be confined inside a subcutaneous implant, facilitating its removal if necessary, and its microvessels will have the capacity to deliver FVIII into the bloodstream of the patient, correcting the clotting deficiency. To develop this technology and make it applicable to hemophilia A, we propose three Specific Aims. In Aim-1, we will determine efficacy of autologous FVIII-secreting implants in an murine immunocompetent model of hemophilia A. In Aim-2, we will determine feasibility of deriving ECFCs and MPCs from hemophilia A patients' peripheral blood. In Aim-3, we will bioengineer FVIII-secreting implants using patients' cells and determine efficient delivery of the factor in xenograft murine models. Collectively, these studies will establish feasibility of using drug-secreting vascular networks to treat a clotting deficiency. We envision this novel approach has the potential to ultimately liberate hemophilia A patients from frequent injections, stringent compliance, and the exorbitant cost of the factor, improving their overall quality of life.